Important note: Information in this article was accurate in March 2000. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, March 2000
Dave Gilden
Even if treatment interruptions are not beneficial in terms of promoting the body’s own immune defenses against HIV, they may have other uses. Keith Henry, who heads the HIV clinic at St. Paul, Minnesota’s public hospital, echoed a common sentiment when he said, "Aggressive treatment looks good for six months, but continuous drugs might not be wise. We have unplanned treatment interruptions by the hundreds. I’ve given up worrying about them unless the therapy is endangered due to drug resistance. You may have to take breaks anyway, just to let the body recoup."
Another year has provided more information concerning the magnitude of long-term drug toxicities, and theories about their causes continue to multiply. The 7th Retrovirus Conference heard a number of reports on the incidence and mechanism of metabolic and physical changes related to fat processing. The negative aspects of treatment are an increasingly attractive reason for taking a break. Still, there is no way of predicting at this point how much a break will reverse the accumulated side effects – or how much damage HIV will do at the same time.
"Lipodystrophy," first noticed in 1996, has always been a confusing topic. It is the rubric under which fall many of the physical and metabolic changes associated with HAART: elevated blood lipids, higher blood sugar and/or insulin, loss of subcutaneous fat (particularly in the limbs, buttocks and cheeks), breast enlargement, growth of fat pads between the shoulder blades ("buffalo hump"), and last but not least, increased deposits of fat around the organs in the abdomen (‘protease paunch"). It has never been clear whether all these sometimes contradictory symptoms are due to the same mechanism, nor how prevalent they are.
Absence of common standards to evaluate the new abnormalities has made it difficult for researchers to compare their frequently contradictory data. At the 7th Retrovirus Conference, a number of large observational studies sought to better gauge the prevalence of the problem. Estimates of the frequency of changes in body fat ranged from 14.3% (poster #13) to about 67% (poster #14). An Australian survey (talk #201) of body fat abnormalities in that country’s HIV population recorded an overall prevalence of 54%, including 63% of those who had taken protease inhibitors and 32% of those with exposure to treatments that did not include PIs. Of those with no history of treatment, 21% showed some physical changes – mostly mild peripheral fat loss. The survey covered 1337 patients, nearly all men. Assessment was largely by physical exam and patient report, with a quarter of the cohort examined by DEXA, an x-ray scanning technique.
People who begin treatment during primary infection syndrome, which occurs just after contracting HIV, might be expected to escape some of the ravages wrought by the virus. They are not immune to disturbances in their fat processing and storage, though. A Spanish study (poster #12) followed 14 men and 3 women whose treatment started during primary infection. The 17 received a combination of d4T, 3TC and indinavir and were followed for a median of 20 months. Six of them (35%) developed some body-shape changes, with the percentage increasing as time went on. About half had high blood cholesterol and/or triglycerides. A recently published logical extension of this study followed 11 HIV-negative men on ritonavir for two weeks (AIDS 14(1):51-7). The men exhibited significant increases in their blood lipids – cholesterol and triglycerides – compared to eight controls who did not take ritonavir.
The general absence of women in many of these studies is frustrating because their pattern of fat metabolism differs from that of men. An update of the SALSA study (poster #26) a survey of 324 HIV+ American men and 71 HIV+ American women with body-shape abnormalities, was presented at the 7th Retrovirus Conference. Based on physicians’ exam and patient self-report, SALSA found that the women tended to have more localized fat accumulation and less subcutaneous fat loss than the men. Elevations in blood cholesterol and triglycerides were one-third to one-half less frequent in the women. Only 63% of the women, compared to 81% of the men, had taken protease inhibitors.
Of course, the SALSA study does not give a picture of the overall frequency of these abnormalities, since it includes only people who already have them. Italian investigators presenting at the Retrovirus Conference (poster #28) reported that the two-year incidence of developing fat tissue aberration among women on protease inhibitors was about 45%, a figure similar to that for men.
Risk factors for developing the signs of lipodystrophy were similar in many of the studies. Generally, longer duration of HIV infection and treatment, lower pretreatment CD4 count or percent, greater viral load drop, older age and elevated blood lipids or thicker fat layers when commencing treatment were predictors of one expression or another of lipodystrophy (poster #23). Among the drugs, indinavir and d4T were sometimes particularly implicated – and sometimes not.
White race also was sometimes associated with greater risk for lipodystrophy, which may explain the low-end 14.3% prevalence estimate mentioned above. That figure came from the Community Programs for Clinical Research on AIDS, which follows a population with more blacks and Hispanics than other studies.
The presence of signs of lipodystrophy in people who never took protease inhibitors has upset the original assumption that all the disturbances were inflicted by the protease inhibitors. These drugs may be the main actors, but nucleoside analogs and NNRTIs could be contributing to different aspects of the problem.
Protease inhibitors were supposedly designed to selectively bind to HIV’s protease enzyme, but they may also bind to and disrupt some of the human molecules involved in removing lipids from the bloodstream and storing them as fat. James Lenhard, Ph.D., a project leader in GlaxoWellcome’s diabetes/obesity unit, made a series of presentations on this subject at the 7th Retrovirus Conference. He found that the effect of the protease inhibitors varied in a specially bred strain of obesity-inclined, HIV- mice. Nelfinavir (poster #39), for example, increased triglycerides but not cholesterol in the mice’s blood while indinavir (poster #38) heightened both. The effect of these protease inhibitors in cell culture reinforced the effects of other compounds known to alter retinoic acid signaling, which promotes the maintenance, proliferation, and maturation of fat cells.
If protease inhibitors are to blame for lipodystrophy, switching to a "protease-sparing" anti-HIV regimen might improve patients’ symptoms. That was usually not apparent in the trials described at the Retrovirus Conference. A Spanish presentation (poster #206) described 48-week results for 108 volunteers who either switched to ddI/d4T/nevirapine or remained on their original d4T/3TC/protease inhibitor regimen. Here, cholesterol and triglyceride levels showed modest improvements with the change to the nevirapine regimen, but body-shape anomalies were no different between the two groups. The trial participants did report a significantly improved quality of life with nevirapine. HIV remained suppressed in 90% of the nevirapine group and 94% of those who continued their PI.
The one study to find appreciable normalization of body-shape was a Glaxo Wellcome-sponsored study (poster #51) in 211 people, 106 of whom exchanged their protease inhibitor for the Glaxo’s nucleoside analog abacavir. The group as a whole started with borderline high blood lipids. Cholesterol levels declined substantially over 24 weeks among those receiving abacavir. In a substudy of just 18 persons with lipodystrophy, three of nine reported improvements in their body-shape while one reported a worsening. All nine remaining on protease inhibitors had worse signs of lipodystrophy at the end of the 24 weeks. Abdominal girth and breast size in particular seemed to decrease in the abacavir group.
One of the reasons that these protease inhibitor discontinuation trials did not have impressive results is that the nucleoside analogs themselves can affect fat metabolism. d4T has received particular blame for this, although several studies (for example, poster #21) at the 7th Retrovirus Conference did not find a particular association with this nucleoside analog. One trial, conducted by Tierry Saint-Marc of Lyon, France, did find that switching from d4T to abacavir, AZT or AZT/3TC reversed some signs of lipodystrophy. Forty-one of his patients were also on protease inhibitors, and 18 originally were receiving just d4T and a second nucleoside analog (ddI or 3TC). After 12 months, 29 of the PI-takers and 15 of those on dual nucleoside analogs had major improvements in subcutaneous fat, both in the limbs and the abdomen. Triglycerides also declined, but other parameters, including visceral fat and cholesterol remained unchanged.
Whether or not d4T is a particular culprit, the Saint-Marc study jibes with the growing feeling (symposium lecture #S21) that nucleoside analogs play some part in the overall long-term toxicity picture. It has been known ever since the introduction of AZT that nucleoside analogs interfere with the functioning of the mitochondria, the cell components that produce energy by means of oxidation. The mitochondria contain some of their own genes, which are duplicated when a mitochondrion replicates within a cell. The enzyme that duplicates the mitochondrial DNA is more primitive than its analog in the cell nucleus. Like HIV’s reverse transcriptase, the mitochondrial enzyme’s activities are interrupted by AZT, ddI and the rest of the nucleoside analogs.
Most of the side effects of nucleoside analogs, including neuropathy, myopathy (muscle wasting), pancreatitis, suppression of white blood cell production in the bone marrow and high lactic acid levels in the blood are thought to arise from mitochondrial dysfunction. If some of the nucleoside analogs affected the mitochondria in fat tissue, it might show up as loss of ability to remove lipids from the bloodstream and create fat. Abnormal fat deposits might then build up in tissues less affected by nucleoside analogs. Similar fat redistribution occurs in Madelung’s disease, a condition unrelated to HIV that is known to result from mitochondrial dysfunction.
There is another reason why the protease inhibitor- to-NNRTI switching studies failed to demonstrate conclusive results. Three of them utilized efavirenz as the NNRTI. It has been noted before (7th Euro. Conf. on Clinical Aspects and Treatment of HIV, Oct. 1999, talk #112) that efavirenz tends to raise blood lipid levels. Glaxo’s James Lenhard observed that efavirenz raised triglyceride and cholesterol levels in the blood and caused liver enlargement in his mouse model (poster #41). Dr. Lenhard discovered that efavirenz, at least at high doses, decreased the mouse liver’s production of enzymes that participate in fat oxidation. This impairment would reinforce the mitochondrial damage caused by nucleoside analogs. High dose efavirenz also had the effect of increasing lipid-synthesizing enzymes in subcutan-eous fat cells.
A University of Wisconsin group reported at the 7th Retrovirus Conference on their observations of impaired arterial wall flexibility in people taking protease inhibitors (poster 29). Twenty-one HIV+ patients receiving protease inhibitors were compared to seven on non-PI regimens. As measured by ultrasound imaging, flow-mediated arterial expansion was much lower in the protease inhibitor receivers. Combined with the PI group’s higher blood lipids, the decreased ability of arterial walls to expand increases these individuals’ risk of heart attacks. Their arteries would be less able to compensate for blood clotting arising after rupture of fatty plaques on arterial walls.
Six studies, though, found no evidence of increased frequency of cardiovascular disease in persons on protease inhibitors, whether by checking hospital records or using ultrasound to measure artery wall thickness. Observation times were very limited, to less than 30 months of PI treatment, which is probably not long enough for heart disease to express itself. The four ultrasound studies did find increased fatty plaques on artery walls of people with HIV compared to their HIV-negative counterparts (poster #30) an observation that may become accentuated as the high lipid levels associated with protease inhibitors continues over the years.
The largest of the cardiovascular disease studies(poster #33) checked the records of 4500 HIV+ members of the huge HMO Kaiser Permanente Northern California. From January 1996 to June 1999, there was no significant difference in coronary heart disease incidence among all patients with HIV, those receiving protease inhibitors and Kaiser’s general membership.
People are still dying from HIV-associated causes, but the long-term side effects of antiretroviral drugs have yet to show themselves in the mortality figures. At the 7th Retrovirus Conference, eight posters looked at mortality statistics. A Seattle survey (poster #464) of 724 persons with AIDS found that treatment with HAART reduced the risk of dying by 60%. A French cohort (poster #461) presented the most extensive and complete results. In its 1143 HIV clinic patients, the death rate declined 75% since the introduction of HAART but was still 9.5 times that of the general population. Causes of death mentioned in these reports are mainly the traditional opportunistic infections plus a growing number of "pre-AIDS" conditions that can also affect HIV-negative persons, usually to a lesser extent. These include hepatitis C, septicemia (blood-borne infections that occur especially among IV drug users), pneumonia and malignancies (including lung cancer).
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